Rongyi Chen1, Ying Sun1, Xiaomeng Cui1, Zongfei Ji1, Xiufang Kong1, Sifan Wu1, Qingrong Huang1, Xiaoming Dai1, Si Zhang2, Lili Ma1, Lindi Jiang3. 1. Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Evidence-Based Medicine Center, Fudan University, China. 2. Key Laboratory of Glycoconjugate Research Ministry of Public Health, Gene Research Center, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. 3. Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Evidence-Based Medicine Center, Fudan University, China. Electronic address: jiang.lindi@zs-hospital.sh.cn.
Abstract
BACKGROUND: Autophagy is a ubiquitous and evolutionarily conserved self-rescue process. Studies have shown that autophagy is involved in the pathogenesis of multiple diseases; however, whether autophagy is associated with the pathogenesis of Takayasu's arteritis (TA), a large vessel idiopathic inflammatory disease characterized by vascular fibrosis, remains unclear. Moreover, although IL-6 is believed to be a direct target for TA treatment, anti-IL-6 treatment could not block TA-associated fibrosis in some cases, which impairs the aortic function of patients and can result in death. Thus, identify the mechanisms associated with TA is extremely important. Based on the relationship between autophagy and IL-6, we investigated the role of autophagy in the vascular fibrosis of TA induced by IL-6. METHODS: Autophagy proteins (LC3 and Atg3), IL-6, and markers of fibrosis (collagen 1 and α-SMA) were detected in tissues with TA lesions via immunochemistry, immunofluorescence, and Western blot, respectively. Different stages of autophagy were analyzed by the specific inhibitors, 3-methyladenosine (early stage), hydroxychloroquine sulfate (late stage), and bafilomycin A1 (late stage). Autophagosomes were detected using electron microscopy and a viral-vector transfection assay. The fibrosis profiles induced by IL-6-dependent autophagy was assessed with an ELISA. RESULTS: The expression of autophagy, IL-6, and fibrosis markers were elevated and correlated with each other in the adventitia tissues of TA patients. Furthermore, exogenous IL-6/IL-6Rα could significantly increase autophagy and fibrosis in vitro. An autophagy inhibitor was found to significantly block both autophagy and fibrosis induced by IL-6. Finally, IL-6 was found to significantly promote autophagy-induced fibrosis through the activation of the Jak1 pathway. CONCLUSIONS: IL-6-induced autophagy plays an important role in vascular fibrosis of TA. Targeting autophagy pathways might represent a novel therapeutic option for the treatment of TA.
BACKGROUND: Autophagy is a ubiquitous and evolutionarily conserved self-rescue process. Studies have shown that autophagy is involved in the pathogenesis of multiple diseases; however, whether autophagy is associated with the pathogenesis of Takayasu's arteritis (TA), a large vessel idiopathic inflammatory disease characterized by vascular fibrosis, remains unclear. Moreover, although IL-6 is believed to be a direct target for TA treatment, anti-IL-6 treatment could not block TA-associated fibrosis in some cases, which impairs the aortic function of patients and can result in death. Thus, identify the mechanisms associated with TA is extremely important. Based on the relationship between autophagy and IL-6, we investigated the role of autophagy in the vascular fibrosis of TA induced by IL-6. METHODS: Autophagy proteins (LC3 and Atg3), IL-6, and markers of fibrosis (collagen 1 and α-SMA) were detected in tissues with TA lesions via immunochemistry, immunofluorescence, and Western blot, respectively. Different stages of autophagy were analyzed by the specific inhibitors, 3-methyladenosine (early stage), hydroxychloroquine sulfate (late stage), and bafilomycin A1 (late stage). Autophagosomes were detected using electron microscopy and a viral-vector transfection assay. The fibrosis profiles induced by IL-6-dependent autophagy was assessed with an ELISA. RESULTS: The expression of autophagy, IL-6, and fibrosis markers were elevated and correlated with each other in the adventitia tissues of TA patients. Furthermore, exogenous IL-6/IL-6Rα could significantly increase autophagy and fibrosis in vitro. An autophagy inhibitor was found to significantly block both autophagy and fibrosis induced by IL-6. Finally, IL-6 was found to significantly promote autophagy-induced fibrosis through the activation of the Jak1 pathway. CONCLUSIONS:IL-6-induced autophagy plays an important role in vascular fibrosis of TA. Targeting autophagy pathways might represent a novel therapeutic option for the treatment of TA.
Authors: Julieta S Del Mauro; Paula D Prince; Yanina Santander Plantamura; Miguel A Allo; Luciano Parola; Nahuel Fernandez Machulsky; Marcela A Morettón; Eliana P Bin; Germán E González; Facundo M Bertera; Andrea Carranza; Gabriela Berg; Carlos A Taira; Martín Donato; Diego A Chiappetta; Ariel H Polizio; Christian Höcht Journal: Hypertens Res Date: 2021-02-22 Impact factor: 3.872
Authors: Maja Stojanovic; Sanvila Raskovic; Vladimir Milivojevic; Rada Miskovic; Ivan Soldatovic; Sanja Stankovic; Ivan Rankovic; Marija Stankovic Stanojevic; Sanja Dragasevic; Miodrag Krstic; Andreas P Diamantopoulos Journal: J Cardiovasc Dev Dis Date: 2021-12-14